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When stem cells meet immunoregulation
No full textThe clinical use of stem cells to prevent tissue injury or reconstruct damaged organs is constrained by different ethical and biological issues. Whereas the use of adult stem cells isolated from differentiated tissues is advantageous from the ethical point of view, the immune response of a host to implants of either embryonic or adult stem cells remains a critical problem. Embryonic stem cells can be rejected by an immunocompetent recipient as well as some types of adult stem cells. There is, however, a population of adult stem cells able to differentiate into the three mesenchymal lineages, osteocytes, chondrocytes, adipocytes that have the additional capacity of modulating the immune response by the activation of disparate mechanisms, among which the generation of antigen-specific CD4(+)CD25(+)FoxP3(+) regulatory T lymphocytes. This short review will focus on the immunological properties of embryonic and adult stem cells are, with particular emphasis on the immunomodulatory function of mesenchymal stem cells and their interactions with regulatory T lymphocytes
Extracellular Vesicles as Natural, Safe and Efficient Drug Delivery Systems
No full textExtracellular vesicles (EVs) are particles naturally released from cells, delimited by a lipid
bilayer, carrying functionally active biological molecules. In addition to their physiological role in
cellular communication, the interest of the scientific community has recently turned to the use of
EVs as vehicles for delivering therapeutic molecules. Several attempts are being made to ameliorate
drug encapsulation and targeting, but these efforts are thwarted if the starting material does not
meet stringent quality criteria. Here, we take a step back to the sources and isolation procedures
that could guarantee significant improvements in the purification of EVs to be used as drug carriers,
highlighting the advantages and shortcomings of each approac
Harnessing Endogenous Cellular Mechanisms for Bone Repair
Full text linkAlthough autologous tissue transplantation represents a valid approach for bone repair, it has encountered crucial barriers in therapeutic translation, not least the invasive process necessary for stem cell isolation. In recent years, the scientific community has made significant strides for identifying new treatment options, and great emphasis has been placed on the tight interaction between skeletal and immune system in modulating the outcome of bone repair. Within the context of specific injury environmental cues, the cross talk among inflammatory cells and tissue resident and/or circulating progenitor cells is crucial to finely coordinate repair and remodeling processes. The appropriate modulation of the inflammatory response can now be considered a new trend in the field of regenerative medicine, as it raises the attracting possibility to enhance endogenous progenitor cell functions, finally leading to tissue repair. Therefore, new treatment options have been developed considering the wide spectrum of bone–inflammation interplay, considering in particular the cell intrinsic cues responsible for the modulation of the injured environment. In this review, we will provide a panoramic overview focusing on novel findings developed to uphold endogenous bone repair
THE DEVELOPMENT OF TISSUE-ENGINEERED BONE OF DIFFERENT ORIGIN THROUGH ENDOCHONDRAL AND INTRAMEMBRANOUS OSSIFICATION FOLLOWING THE IMPLANTATION OF MESENCHYMAL STEM CELLS AND OSTEOBLASTS IN A MURINE MODEL.
No full textThe study of host cell recruitment by implanted exogenous cells is one of the novel challenges in tissue engineering. We previously reported the development of tissue-engineered bone deposited by host cells in porous ceramic scaffolds seeded with murine mesenchymal stem cells (MSC) and implanted in immunocompromised mice. To better highlight the contribution of host cells to the development of the engineered tissue and to investigate whether the capacity to recruit host cells was dependent on the donor cell commitment, we implanted ceramic scaffolds seeded with either murine GFP labeled MSC or GFP labeled osteoblasts (OB) into immunocompromised mice. Although we observed formation of bone in all scaffolds, the origin of bone cells and the ossification type were strictly dependent on the nature and commitment of the seeded cells. MSC implants led to formation of bone of host origin through the activation of an endochondral ossification process while an intramembranous ossification directly performed by the seeded cells was observed in OB implants. Moreover, we observed an increased vascularization in MSC implants due to the higher capacity of MSC to recruit host CD31+ endothelial cells. The relationship between this enhanced vascularization and the type of ossification is discussed.The study of host cell recruitment by implanted exogenous cells is one of the novel challenges in tissue engineering. We previously reported the development of tissue-engineered bone deposited by host cells in porous ceramic scaffolds seeded with murine mesenchymal stem cells (MSC) and implanted in immunocompromised mice. To better highlight the contribution of host cells to the development of the engineered tissue and to investigate whether the capacity to recruit host cells was dependent on the donor cell commitment, we implanted ceramic scaffolds seeded with either murine GFP labeled MSC or GFP labeled osteoblasts (OB) into immunocompromised mice. Although we observed formation of bone in all scaffolds, the origin of bone cells and the ossification type were strictly dependent on the nature and commitment of the seeded cells. MSC implants led to formation of bone of host origin through the activation of an endochondral ossification process while an intramembranous ossification directly performed by the seeded cells was observed in OB implants. Moreover, we observed an increased vascularization in MSC implants due to the higher capacity of MSC to recruit host CD31+ endothelial cells. The relationship between this enhanced vascularization and the type of ossification is discussed. © 2009 Elsevier Ltd. All rights reserved
The recruitment of two consecutive and different waves of host stem/progenitor cells during the development of tissue-engineered bone in a murine model
No full textAngiogenesis plays a central role in bone regeneration, not only for the transport of nutrients, but also for locally directing skeletal stem/progenitor cells. Following ectopic implantation of porous ceramic cubes seeded with mouse GFP-labeled mesenchymal stem cells (MSC) into syngenic mice, we investigated the cascade of events leading to bone formation. Implants harvested at different times were enzymatically digested to generate single-cell suspensions. Recovered cells were sorted to separate GFP+implanted MSC and host recruited GFP- cells. We isolated and characterized two different waves of cells, migrating from the host to the MSC-seeded ceramic. The first migrated cell population, recovered 7 days after implantation, was enriched in CD31+endothelial progenitors, while the second one, recruited at day 11, was enriched in CD146+pericyte-like cells. Both populations were not recruited into the scaffold following implantation of a non-MSC seeded ceramic. Pericyte-like cell mobilization was dependent on the first migrated endothelial cell population. Pericyte-like cells retained properties distinctive of stem cells, such as capacity of performing a high number of in vitro cell divisions and showed an osteogenic potential. Studies on the cross talk between implanted exogenous MSC and resident stem/progenitor cells could open new perspectives for future clinical applications
Mesenchymal stem cells paracrine activity is modulated by platelet lysate: induction of an inflammatory response and secretion of factors maintaining macrophages in a pro-inflammatory phenotype.
No full textEditorial: bone and cartilage regeneration with extracellular vesicles
No full textThe primary aim of regenerative medicine is to stimulate tissue healing. Despite the great promises raised by the use of stem/progenitor cells for skeletal tissue regeneration, cell tracking analysis has revealed that transplanted cells do not commonly become part of the injured tissue (Pittenger et al., 2019). The role of the stem cell-derived secretome is becoming increasingly intriguing due to its ability to stimulate endogenous regenerative processes. Therefore, the so-called “paracrine hypothesis” has taken hold (Gnecchi et al., 2016). Extracellular vesicles (EVs) are important components of the cell secretome, representing promising tools for the delivery of biologically active molecules which can be used for therapeutic purposes (Alcaraz et al., 2019). EVs are bilayer membrane fragments released by almost any cell type upon activation or death. Two major types of EVs are usually distinguished: exosomes, formed from the endosomal cell compartment, and microvesicles, produced by the direct extrusion from the cell plasma membrane (Doyle and Wang, 2019). Nowadays, the effects specifically exerted by one EV subpopulation over another are still unclear. This is in part due to their overlapping size and variable cargos, which does not allow a precise discrimination between them. EVs contain proteins, lipids, and nucleic acids and have the potential to activate not only complementary, pro-regenerative signaling pathways in the same responder cells, but also to stimulate multiple target cell populations and tissues. This property could make them an efficient therapeutic vehicle for bone and cartilage regenerative medicine. However, there are many concerns that should be addressed, such as the development of strategies to obtain sufficient amounts of EVs, the identification and characterization of the optimal donor cell source, the necessity to develop ideal scaffolds to be used as depots for controlled release of EVs, as well as the need to better understand the mechanisms underlying bone/cartilage formation after EV treatment
The Regenerative Role of the Fetal and Adult Stem Cell Secretome
No full textFor a long time, the stem cell regenerative paradigm has been based on the assumption that progenitor cells play a critical role in tissue repair by means of their plasticity and differentiation potential. However, recent works suggest that the mechanism underlying the benefits of stem cell transplantation might relate to a paracrine modulatory effect rather than the replacement of affected cells at the site of injury. Therefore, mounting evidence that stem cells may act as a reservoir of trophic signals released to modulate the surrounding tissue has led to a paradigm shift in regenerative medicine. Attention has been shifted from analysis of the stem cell genome to understanding the stem cell “secretome”, which is represented by the growth factors, cytokines and chemokines produced through paracrine secretion. Insights into paracrine-mediated repair support a new approach in regenerative medicine and the isolation and administration of specific stem cell-derived paracrine factors may represent an extremely promising strategy, introducing paracrine-based therapy as a novel and feasible clinical application. In this review, we will discuss the regenerative potential of fetal and adult stem cells, with particular attention to their secretome
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